1. Technical Field of the Invention
The present invention relates to a process for preparing 2-methylpyrrolidine compounds, specific enantiomers, and derivatives thereof. More particularly, the invention relates to a process for preparing a specific isomer of 2-methylpyrrolidine from a chiral starting material.
2. Description of the Related Technology
Pyrrolidine ring systems and their derivatives often are present in many biologically important substances. 2-Methylpyrrolidine, in particular, is a compound useful as a starting material in various pharmaceutical processes. For example, 2-methylpyrrolidine has demonstrated usefulness as a starting material in the preparation of H3 receptor ligands. International Publication WO 02/074758, published Sep. 26, 2002, describes the preparation of cyclic amines attached to a benzofliran moiety via an alkyl chain. Such compounds have demonstrated beneficial effects for treatment of H3-mediated conditions or diseases, for example, cognitive function or obesity, among other conditions and diseases.
Processes for preparing 2-methylpyrrolidine have been reported in the literature. For example, Elworthy, et al. report in Tetrahedron, Vol. 50, No. 20, pp. 6089–6096 (1994) a process for preparing 2-methylpyrrolidines via the alkylation of α-lithio pyrrolidine derivatives. Andres, et al. describe in Eur. J. Org. Chem., pp. 1719–1726 (2000) the removal of an N-benzyl moiety by hydrogenolysis over palladium on carbon and treatment with tosyl chloride of (2R)-2-[(2′R)-2′-methyl-N-pyrrolidinyl]-2-phenyl-1-ethanol. Nijhuis, et al. suggest in J. Org. Chem., Vol. 54, No. 1, pp. 209–216 (1989) that optically active pyrrolidines can be prepared from prolinol via a salt of 2-chloromethyl(pyrrolidine). In addition, Donner, et al. describe a process for preparing enantiomerically pure 2-methylpyrrolidine via Raney nickel reduction of a N-Boc-protected prolinol thioether derivative in Tetrahedron Letters, Vol. 36, No. 8, pp. 1223–1226 (1995). Although these methods can provide optically active pyrrolidine derivatives under some conditions, the preparation of compounds via such processes in large quantities generally is not optimally cost-effective for commercial utility.
Accordingly, significant reliance on methods of resolving racemic 2-methylpyrrolidine to obtain a single desired enantiomer exists in the pharmaceutical industry. For example, racemic mixtures have been resolved by forming diasteromeric salts with a chiral acid, such as tartaric acid. (See, for example, Elworthy, et al., Tetrahedron, Vol. 50, No. 20, pp. 6089–6096 (1994)). Racemic mixtures also have been separated by the attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5th edition (1989); and Longman Scientific & Technical, Essex CM20 2JE, England. In addition, direct separation of a mixture of optical enantiomers on chiral chromatographic columns or by fractional recrystallization also has been a commonly employed in the art. Unfortunately, these methods often result in the inefficient use and undue waste of valuable starting materials, which render such processes less effective for commercially viable processes for preparing an optically active compound.
Accordingly, it would be beneficial to provide an efficient, cost-effective synthesis of 2-methylpyrrolidine. In addition, it would be beneficial to provide a process for obtaining a specific enantiomer of 2-methylpyrrolidine via such efficient, cost-effective synthesis.